Despite four decades of research concerning cardiac arrest/CPR, clinical outcome remains poor. Only about 5% of individuals who suffer cardiac arrest are successfully resuscitated to the extent that they are returned to productive lives, and neurologic and neuropsychologic deficiencies remain prevalent in the remaining 95% of patients. Women are at lower risk than men for cardiovascular disease, including stroke (focal cerebral ischemia), yet cerebral ischemic events do occur in both sexes at all ages. Although women have less sudden cardiac death than men, survival differences and neurologic and neuropsychologic evaluations between men and women after cardiac arrest have not been closely examined. The vasoactive hormone, estrogen, has historically been considered to be protective in coronary heart disease, but it is not clear if the steroid is also an important neuroprotectant in either women or men. More critically, the comparative vulnerability of females and males to brain tissue injury once cardiac arrest/CPR is ongoing remains unknown. Our preliminary findings suggest that brains of females are better protected from cardiac arrest/CPR than males, and that estrogen may be involved with this neuroprotection. While protection conferred by estrogen is biologically feasible, specific neuroprotective mechanisms are unknown. The goal of this project is to determine if there are inherent sex-linked neural injury mechanisms in experimental cardiac arrest/CPR, and if 17a-estradiol, the principal biologically active estrogen in mammals, plays a key role in salvaging brain tissue after cardiac arrest/CPR. In Aim 1, we will determine if histopathological and neurobehavioral outcomes after cardiac arrest/CPR are more favorable in female vs male mice, and if exogenous estrogen is the source of neuroprotection. In Aim 2, we will determine if neural injury from cardiac arrest/CPR is exacerbated in transgenic mice deficient in estrogen receptors (estrogen receptor knockouts). Finally, we will examine a neuronal mechanism, hypothesizing that estrogen reduces tissue injury from cardiac arrest/CPR by a Bcl-2 mediated mechanism which is dependent on nuclear estrogen receptors. The proposed study will contribute to our understanding of neurological injury resulting from cardiac arrest/CPR in females and the role of estrogen as a potential neuroprotective therapy for patients of either sex.